Opioids are classically viewed as having analgesic actions with little-to-no anti-inflammatory activity. It is generally recognized that opioids produce analgesia through activation of receptors located in the central nervous system (CNS) at both spinal and supraspinal levels. However, recent studies indicate that opioids also act in the periphery to suppress sensitized nociceptive afferent nerve fibers and to produce a peripherally-mediated antinociception. These observations that opioids act in inflamed tissue to produce antinociception suggest that they may also act to alter the development of tissue inflammation. A possible anti-inflammatory action of opioids is supported by several lines of evidence. For example, opioid receptors have been reported to be present on peripheral afferent and sympathetic fibers, and leukocytes, all of which are thought to be involved in inflammation. In addition, peripheral effects of opioids on plasma extravasation have been demonstrated using an animal preparation involving electrical stimulation of the saphenous nerve. Furthermore, recent studies using actual models of inflammation have demonstrated that opioids suppress edema, hyperthermia and plasma extravasation, in parallel to their reduction of hyperalgesia. These anti-inflammatory opioids are stereospecific, dose-related and naltrexone-reversible [see preliminary results]. However, the opioid receptor subtype mediating these anti-inflammatory effects and the site/mechanism of action undetermined. This proposal will extend our knowledge in this area by characterizing the receptor sub-type mediating the anti-inflammatory effects of opioids and determining its mechanism of action. Specifically, the proposed studies will evaluate the effects of opioids on carrageenan-induced edema, hyperthermia, plasma extravasation and hyperalgesia. In addition, opioid suppression of released levels of inflammatory mediators will be evaluated using microdialysis probes implanted into the hindpaws of rats injected with carrageenan. The proposed studies will: 1) determine the receptor sub-type(s) mediating anti-inflammatory actions of opioids and their location by comparing ED50 values of mu, delta and kappa selective opioids after peripheral (ipl), systemic (ip) or central (icv) administration; 2) determine whether the anti-inflammatory . action of opioids is due to suppression of primary afferent nociceptor fiber activity; 3) determine whether the anti-inflammatory action of opioids is due to suppression of leukocyte activity; and 4) determine whether the anti-inflammatory action of opioids is due to suppression of sympathetic fiber activity.